The activation of zinc metal is important as unactivated zinc is generally unreactive and so activation is necessary for the preparation of organozinc reagents that are useful for the preparation of a number of different classes of compounds.
A number of techniques for the activation of zinc have been reported in the prior art. Metzeger et al. (Organic Letters, 2008, 10, 1107-1110) report activation of zinc dust (which is an optimum form of this reagent due to its high surface area) using a combination of 1,2-dibromoethane (classified as carcinogenic) and trimethylsilyl chloride. With added lithium chloride, this allows the formation of organozinc halides in tetrahydrofuran (THF) solution. The use of 1,2-dibromoethane, a carcinogen, makes this process practically disadvantageous.
Huo (Organic Letters, 2003, 3, 423-425) discloses the formation of organozinc halides using zinc metal of a variety of particle sizes in which a polar, aprotic, coordinating and nucleophilic solvent (such as N,N-dimethylacetamide) is used along with a sub-stoichiometric amount of iodine for activation. This avoids the problem associated with the process of Metzeger et al. of the use of a carcinogenic solvent. However, the very polar aprotic solvents used in the activation process such as N,N-dimethylacetamide can often hamper or react with the reactants or additives used in subsequent reactions of the organozinc halide. The strong dipole that enables the strong coordination properties of the solvent that make it effective at solvating the zinc complexes that are formed during the activation process can also cause a high nucleophilicity that can cause an unwanted reaction with an electrophile. For example, N,N-dimethylacetamide is well known to react with acid chlorides, which are common substrates for reactions with organozinc reagents.
It would therefore be a considerable advantage if these various problems that exist with the prior art zinc activation methods could be overcome. Firstly, any new method should not involve the activation of zinc dust using 1,2-dibromoethane or another carcinogen. Secondly, it is often desirable to separate the formed organozinc halide from excess zinc metal to prevent unwanted side-reactions in subsequent steps. Being able to use coarser zinc power/granules which can easily be separated from the zinc reagent would therefore be advantageous. Thirdly, a new methodology which would allow the use of less reactive solvents, typically of reduced polarity, would offer an advantage in reactions of the organozinc reagent where additives or other reactants could react with or be hampered by polar, aprotic solvents such as N,N-dimethylacetamide and would therefore overcome the limitations of the method described by Huo.